Upadacitinib in Giant Cell Arteritis
Upadacitinib 15 mg daily is an effective treatment option for GCA, particularly for patients with refractory disease or those who have failed tocilizumab or methotrexate, though it is not currently included in the 2021 ACR/Vasculitis Foundation guidelines as these predate the pivotal trial data. 1
Current Guideline Recommendations
The 2021 ACR/Vasculitis Foundation guidelines do not mention upadacitinib or other JAK inhibitors for GCA management, as these guidelines were published before the phase 3 trial data became available. 2 The guidelines recommend:
- First-line glucocorticoid-sparing therapy: Tocilizumab combined with glucocorticoids over glucocorticoids alone for newly diagnosed GCA 2
- For refractory disease: Adding tocilizumab over methotrexate for disease relapse with cranial ischemia 2
- Alternative options: Methotrexate can be considered when tocilizumab is contraindicated due to recurrent infections, gastrointestinal perforations, diverticulitis, or cost 2
Evidence for Upadacitinib
Phase 3 Trial Data (SELECT-GCA)
The most recent and highest-quality evidence comes from a 2025 phase 3 randomized controlled trial that demonstrated:
- Upadacitinib 15 mg daily achieved sustained remission in 46.4% of patients versus 29.0% with placebo (P = 0.002) 1
- This was achieved with a 26-week glucocorticoid taper (versus 52-week taper in placebo group) 1
- Upadacitinib 7.5 mg daily was NOT superior to placebo (41.1% remission rate) 1
- The 15 mg dose was superior for sustained complete remission, time to flare, cumulative glucocorticoid exposure, and patient-reported outcomes 1
- Safety profile was similar to placebo during the 52-week treatment period, with no major adverse cardiovascular events in the upadacitinib groups 1
Real-World Evidence
Multiple real-world studies support upadacitinib's efficacy:
- A 2024 multicenter retrospective analysis of 35 GCA patients treated with JAK inhibitors (including 10 with upadacitinib) showed 57% achieved clinical remission and 46% achieved complete remission after median 11 months follow-up 3
- These patients had previously failed conventional immunosuppressants (63%) and biologics including tocilizumab (86%) 3
- A 2023 Swedish case series of 15 GCA patients treated with baricitinib/tofacitinib showed significant CRP reduction at 3 months (p=0.02) and prednisolone dose reduction at 3 months (p=0.02), with no GCA relapses observed 4
Clinical Application Algorithm
When to Consider Upadacitinib
Primary indications:
- Refractory GCA despite tocilizumab therapy 5, 3
- Intolerance to tocilizumab (severe adverse events, recurrent infections) 5
- Relapsing disease after failure of both tocilizumab and methotrexate 3
- Need for accelerated glucocorticoid taper due to steroid-related complications 1
Dosing Strategy
Use upadacitinib 15 mg orally once daily - the 7.5 mg dose has not demonstrated superiority over placebo 1
Combine with a 26-week glucocorticoid taper rather than the traditional 52-week taper 1
Monitoring Requirements
- Assess clinical symptoms (headache, jaw claudication, visual changes) and inflammatory markers (ESR, CRP) regularly 6, 7
- Monitor for serious infections, as 11% of patients in real-world studies discontinued JAK inhibitors due to serious adverse events 3
- Two patients in the Swedish series experienced serious infections but successfully continued or reintroduced therapy after recovery 4
Important Caveats
Cardiovascular Considerations
While cardiovascular risk is a theoretical concern with JAK inhibitors, the phase 3 trial showed no major adverse cardiovascular events in upadacitinib-treated patients 1. However, patients with hypertension and coronary artery disease require close monitoring during treatment 6.
Position in Treatment Algorithm
Upadacitinib should be considered after failure of established therapies (tocilizumab, methotrexate) rather than as first-line therapy, given that current guidelines prioritize tocilizumab and the phase 3 trial included patients both with and without prior tocilizumab exposure 1, 3. The 2021 ACR guidelines do not include JAK inhibitors because they predate this evidence 2.
Regulatory Status
Upadacitinib has been approved by both the European Commission and FDA for GCA treatment, making it a viable option when standard therapies fail 5.